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Close the book on another potential Alzheimer’s therapeutic. The large TOMMORROW Alzheimer’s prevention study failed an interim futility analysis and will shut down, Takeda Pharmaceutical Company Ltd. announced in a press release today. TOMMORROW tested the ability of the drug pioglitazone to delay progression to mild cognitive impairment in people at genetic risk for Alzheimer’s disease. The company cited an “inadequate treatment effect” of pioglitazone for its decision, but did not provide numbers. Robert Alexander at Takeda said that the company hopes to release full findings later this year when analysis has been completed.

Others in the field expressed disappointment at the results but not surprise. “It’s a sad day for all who are interested in AD prevention,” John Breitner at McGill University, Montreal, wrote to Alzforum. Paul Aisen at the University of Southern California, San Diego, agreed. He added, “I am sure a full analysis of the data collected will nonetheless advance the field; we always learn from studies whether positive or negative.”

TOMMORROW is the first of the current generation of Alzheimer’s prevention studies to report results. It differs from most others in important aspects, including how it selected participants, measured outcome, and in its choice of drug (Aug 2013 conference news; Dec 2014 conference news).

“These key differences in design make it difficult to say if the negative results from the TOMMORROW trial are likely to extend to the other prevention trials,” Gad Marshall at Brigham and Women’s Hospital, Boston, wrote to Alzforum (see comment below). Others concurred. “This does not forecast a bad outcome for other trials, but also does not point to a clear path for success,” said Jeffrey Cummings at the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas, who ran one of the clinical sites for the trial.

TOMMORROW enrolled 3,494 cognitively normal participants based on their ApoE and TOMM40 genotype. Alexander noted that to find them, researchers at the 50 clinical sites had to screen about 25,000 people. “We learned a lot about how to identify participants and motivate them to remain in a trial over a long period of time,” he added. Takeda presented some data about the trial’s parameters and retention last December at CTAD and will present a fuller picture this July at AAIC.

One of the study’s goals was to test how well the genetic algorithm succeeded at identifying the people most at risk for progression to MCI, and those data are still being collected, Alexander said. The algorithm applies a controversial finding that a long poly-T repeat in the mitochondrial TOMM40 gene lowers the age of AD onset by about seven years (Jul 2010 conference news; Roses et al., 2010).

Unlike other current prevention trials, TOMMORROW did not test an anti-amyloid therapy. Pioglitazone and related compounds such as rosiglitazone are diabetes drugs that had been abandoned for symptomatic AD treatment based on negative trials, although they did appear to improve brain metabolism, which falters in early AD (Dec 2002 webinar; Sep 2010 news; Dec 2012 news).

TOMMORROW’s outcome measure diverged from those of other ongoing prevention trials in that it used time to progression to MCI-AD, rather than measuring cognitive decline. “[That] is a tough [outcome] to achieve and usually requires a lot more power. All of the other prevention trials use a sensitive global cognitive measure with a continuous score, or a combination of a cognitive measure and progression to MCI,” Marshall wrote. Aisen stressed this as well, noting, “There is no clear line dividing normal cognitive status from MCI, so this endpoint requires the definition and operationalization of a somewhat artificial construct.”

Takeda ran the TOMMORROW study in partnership with Zinfandel Pharmaceuticals, a start-up founded by the late Allen Roses of Duke University. In 1993, Roses discovered the effect of ApoE4 on Alzheimer’s risk, which was widely confirmed. Ann Saunders, who heads Zinfandel and was married to Roses, told Alzforum the company is exploring other opportunities in AD research, though Zinfandel does not have a website describing preclinical or clinical programs. In the meantime, Zinfandel remains committed to sharing the data from the TOMMORROW study with the scientific community, Saunders said.

Other researchers look forward to mining the data. “I am hopeful that the field will be able to leverage these learnings to inform the design of Alzheimer’s prevention trials moving forward,” Jessica Langbaum at Banner Alzheimer’s Institute in Phoenix wrote to Alzforum (see comment below).—Madolyn Bowman Rogers

Comments

These news are certainly disappointing. TOMMORROW was the first of a series of new secondary prevention trials in AD to be completed, albeit early.

TOMMORROW’s design is different in many ways from the other trials out there: DIAN-TU, API-ADAD in the Colombian kindred, API Generation I (APOE4 homozygotes), API Generation II (APOE4 heterozygotes who are amyloid-positive), A4 (amyloid-positive cognitively normal), and EARLY (amyloid-positive cognitively normal with a family history of dementia requirement for younger participants).

TOMMORROW used two risk genes to enrich its sample (APOE4 carrier [heterozygote or homozygote] and TOMM40 carriers) but no amyloid status. This is most similar to the Generation I, which only uses genetic risk (and age) to enrich the sample; however, the risk is greater with the Generation I sample because those participants are APOE4 homozygotes.

Another big difference is the drug used in TOMMORROW, pioglitazone, which is a diabetes medication with therapeutic potential in AD. All of the other prevention trials are using amyloid-modifying drugs (primarily monoclonal antibodies against amyloid, but also BACE inhibitors and one active vaccine against amyloid).

Finally, the primary outcome in the TOMMORROW trial was progression from normal to MCI, which is a tough one to achieve and usually requires a lot more power. All of the other prevention trials use a sensitive global cognitive measure with a continuous score or a combination of a cognitive measure and progression to MCI (but not progression to MCI alone).

These key differences in design make it difficult to say if the negative results from the TOMMORROW trial are likely to extend to the other prevention trials.

On a positive note, it was encouraging and commendable to see that a challenging secondary prevention trial like TOMMORROW can be performed as a proof of concept for this type of new trial in AD. We will certainly have the opportunity to learn a lot from this trial despite the negative treatment results.

The TOMMORROW program should be commended for taking on such an ambitious trial—enrolling such a large number of participants is a remarkable accomplishment. While the announcement to discontinue the study is disappointing, I remain encouraged that the field will learn a great deal as data is shared with the scientific community as part of Takeda and Zinfandel’s commitment to adhere to the Collaboration for Alzheimer’s Prevention (CAP) data and sample sharing principles. I am hopeful that the field will be able to leverage these learnings to inform the design of Alzheimer’s prevention trials moving forward.

The failure of the TOMMORROW preventive trial is not a surprise. Although the concept that AD has to be prevented rather than cured is innovative and deserves to be pursued in the future, we are far from having tools to select the population to be treated, particularly when considering polymorphisms such as ApoE-TOMM40 (but also all genes associated with AD found in recent GWAS studies). Polymorphisms confer a small increased risk of developing MCI-AD together with many other environmental factors, which have not been considered in this trial.

In addition, dealing with MCI-AD we have to consider that the outcome measures to test drug efficacy are poor. The transition from normal to MCI-AD may take many years to occur, giving false negatives at interim analyses.

In conclusion, in my view, the discontinuation should not be considered a failure but instead an opportunity to better design future preventive clinical trials.

It is always very disappointing when a major effort to test an intervention aiming to slow the AD process ends without evidence of efficacy. I am sure that a full analysis of the data collected will nonetheless advance the field; we always learn from studies, whether positive or negative.

I cannot comment specifically on the futility analysis that led to early termination of the trial without knowing the details. But I will say that futility analyses should be performed with great caution, since early, incomplete trial data may not provide an accurate representation of a full data set.

I am concerned that the use of a clinical endpoint, time to diagnosis of MCI due to AD, may not be optimal. There is no clear line dividing normal cognitive status from MCI, so this endpoint requires the definition and operationalization of a somewhat artificial construct. There is substantially more information to be gained from repeated measurement of continuous scales (such as cognitive assessments); in my view, this approach provides a more powerful tool to assess treatment effects.